Cancer is one of the leading causes of death in the United States. The growth and spread of many cancers is driven by genes that are specifically activated in tumors. In many cases, these genes encode proteins involved in metabolism and signaling. Pgrmc1 (progesterone receptor membrane component 1) is a low molecular weight (approximately 25 kDa) protein that was originally thought to be a progesterone receptor. However, it has been demonstrated that Pgrmc1 does not contain any homology to steroid receptors, but instead has homology to cytochrome b5. Pgrmc1 binds to heme and has reducing activity, as the cytochrome proteins do.
Pgrmc1 is over-expressed in multiple types of cancer, including breast, thyroid, colon, ovary and lung cancer. Accordingly, Pgrmc1 has great potential as a biomarker. In breast cancer, Pgrmc1 phosphorylation corresponds with estrogen receptor status, and Pgrmc1 levels correlate with tumor grade in ovarian cancer. Pgrmc1 is also part of a gene signature that predicts hypoxia in breast cancer. Pgrmc1 is also induced during dioxin-induced tumorigenesis and is part of a six gene signature associated with non-genotoxic carcinogens.
These findings are important because they indicate that Pgrmc1 is induced during tumor formation and is up-regulated in tumors in the clinic. One important function of Pgrmc1 in cancer is in chemotherapy resistance. The yeast Pgrmc1 homologue, Dap1 (damage-associated protein), was identified through its role in resistance to chemotherapy. In cancer cells, Pgrmc1 regulates survival in response to chemotherapeutic drugs, both in breast and ovarian cancer cells.
Like cytochrome proteins, Pgrmc1 binds to heme and to P450 proteins, a large class of proteins that are important in drug metabolism, hormone synthesis and metabolism, and lipid synthesis. Pgrmc1 also binds to the cholesterol regulators Insig (insulin-induced gene) and Scap (sterol regulatory element binding protein cleavage activating protein), and to the RNA binding protein PAIR-BP1 (plasminogen activator inhibitor 1 mRNA binding protein), although its biological roles in these interactions is unclear. Indeed, Pgrmc1 does not regulate cholesterol synthesis in cancer cells and has a minimal effect on P450 activity. In contrast, Pgrmc1 has an important role in cell signaling.
Multiple studies have indicated a role for Pgrmc1 in cell signaling. The Pgrmc1 sequence has binding sites for SH2 and SH3 domain-containing proteins and consensus phosphorylation sites for tyrosine kinases. Our laboratory has also shown a more direct role for Pgrmc1 in signaling. When damaged, breast cancer cells suppress death by sustaining signaling through multiple protein kinases, including the serine-threonine kinase Akt, and Pgrmc1 promotes Akt activation. This work was subsequently verified by another group from Germany. Akt is activated by multiple pathways, including the stimulation of receptor tyrosine kinases. This led us to determine the extent to which Pgrmc1 regulates receptor tyrosine kinases in cancer cells, and we have found that Pgrmc1 binds to receptor tyrosine kinases and stabilizes them at the plasma membrane.
Tyrosine kinases span the cell membrane and transmit signals from extracellular polypeptide hormones. Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been linked to increased proliferation, angiogenesis, metastasis and decreased apoptosis (Ritter et al., (2003) Semin Oncol, 30:3-11). The earliest studies with EGFR involved an activated form of the receptor expressed from transforming viruses (De Larco et al., (1980) J Biol Chem, 255:3685-3690), and EGFR is up-regulated in a variety of tumors, including colorectal cancer (72-82%), head and neck cancer (95-100%), breast cancer (14-91%) and renal cell cancer (59-90% (Saloman et al., (1995) Crit Rev Oncol Hematol, 19:183-232). Furthermore, EGFR and HER2/neu over-expression are associated with a poor prognosis in multiple tumor types (Brabender et al., (2001) Clin Cancer Res., 7:1850-1855).
EGFR is inhibited by a growing number of drugs, including the antibody fragments cetuximab, matuzumab, nimotuzumab, zalutumumab and panitumumab and the small molecule inhibitors erlotinib (Tarceva/OSI-774) and gefitinib (Ono et al., (2006) Clin Cancer Res, 12:7242-7251; Bareschino et al., (2007) Ann Oncol, 18 Suppl 6:vi35-41). EGFR inhibitors have promise for treating cancer, but there effectiveness has been limited clinically. EGFR inhibitors such as erlotinib are effective only in a subset of patients that express mutated forms of the receptor. The most prominent group of patients with these mutations is females that have never smoked, leaving many patients with few therapeutic options. A method of inhibiting the progression of cancers is needed, which utilizes small molecule ligands to Pgrmc1.